Is methotrexate (MTX) cleared through hemodialysis (HD) in a patient with impaired renal function?

Methotrexate Clearance by Hemodialysis

Yes, methotrexate can be effectively cleared by hemodialysis, but only when using high-flux dialyzers with extended treatment sessions, and conventional low-flux hemodialysis or peritoneal dialysis is generally ineffective. 1

Evidence for Hemodialysis Clearance

High-Flux Hemodialysis is Effective

• High-flux hemodialysis achieves significant methotrexate clearance with mean plasma clearance rates of 92.1 ± 10.3 mL/min, removing approximately 63% of a high-dose methotrexate load (7.2 g/m²) during a single 6-hour session. 2

• Extended duration sessions (4-6 hours daily) using high-flux dialyzers (such as Fresenius F-80) can reduce methotrexate concentrations from toxic levels (>1,700 μmol/L) to safe levels (<0.3 μmol/L) within 5-6 days in functionally anephric patients. 2

• The median elimination half-life of methotrexate during high-flux hemodialysis or hemodiafiltration is approximately 4.4 hours (IQR 3.8-5.3 hours), demonstrating effective drug removal. 3

Conventional Dialysis is Ineffective

• The FDA label explicitly states that "neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination" when referring to conventional dialysis techniques. 1

• This distinction is critical: only high-flux dialyzers provide adequate clearance, while standard low-flux membranes are ineffective. 1, 2

Critical Clinical Considerations

Rebound Phenomenon

• Methotrexate concentrations rebound by approximately 40% of trough levels after each dialysis session ends, requiring multiple repeated sessions rather than a single treatment. 3

• This rebound occurs because methotrexate redistributes from tissue compartments back into plasma after dialysis stops, necessitating daily sessions until levels remain sufficiently low. 3

Combined Modalities

• Combining hemodialysis with charcoal hemoperfusion can enhance clearance further, achieving 73% reduction in methotrexate concentration through hemodialysis and an additional 37% through hemoperfusion. 4

• This combined approach reduced methotrexate from 390 μmol/L to 7 μmol/L over 24.5 hours of hemodialysis plus 39.5 hours of hemoperfusion, completely preventing gastrointestinal and hematologic toxicity. 4

Treatment Protocol for Methotrexate Toxicity with Renal Failure

Immediate Management

• Administer leucovorin (folinic acid) immediately at 10-100 mg/m² IV every 6 hours, as this is the cornerstone antidote and must be given before considering dialysis. 1, 5

• Initiate aggressive IV hydration and urinary alkalinization with sodium bicarbonate to enhance renal elimination and prevent methotrexate precipitation in renal tubules. 1

Dialysis Indications and Technique

• Consider high-flux hemodialysis when methotrexate levels remain dangerously elevated despite leucovorin rescue, particularly when levels exceed 10 μmol/L at 42 hours post-dose or in patients with severe renal impairment. 1, 2

• Use high-flux dialyzers (not conventional membranes) for 4-6 hours daily, continuing until methotrexate levels fall below 0.05 μmol/L (0.3 μmol/L in some protocols). 2, 3

• Plan for multiple consecutive daily dialysis sessions due to the predictable rebound phenomenon, rather than expecting a single session to be sufficient. 3

Alternative: Glucarpidase

• Glucarpidase is the FDA-approved treatment for toxic methotrexate concentrations with delayed clearance due to impaired renal function, and should be considered when available, especially if methotrexate levels exceed 10 μmol/L at 42 hours. 1, 6

• Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for the enzyme and will be degraded. 1

• Glucarpidase combined with continuous dialysis has achieved recovery from anuric acute kidney injury when conventional therapy failed. 6

Common Pitfalls to Avoid

• Do not assume conventional hemodialysis will be effective—only high-flux dialyzers provide adequate methotrexate clearance. 1, 2

• Do not stop dialysis after a single session when methotrexate levels drop, as rebound will occur; continue daily sessions until levels remain low without further treatment. 3

• Do not delay leucovorin administration while arranging dialysis, as leucovorin efficacy diminishes dramatically after 24 hours and remains the primary antidote. 1, 5

• Do not use folic acid instead of folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block. 5, 7

Prevention in Patients with Renal Impairment

• Patients with creatinine clearance 20-50 mL/min require 50% dose reduction of methotrexate before administration to prevent toxicity. 5

• Methotrexate is contraindicated in patients with significant renal impairment according to traditional guidelines, though high-flux hemodialysis makes treatment feasible when curative therapy is required. 8, 9

• Enhanced monitoring every 2-4 weeks and mandatory folic acid supplementation (1-5 mg daily except on methotrexate day) are essential for patients with any degree of renal impairment. 5, 7